The literature is replete with descriptions of long acting preparations of steroid hormones. Increased duration of activity has generally been achieved by chemical alteration of the parent molecule which, when injected intramuscularly, will form a depot. The injection provides biological effects spanning several weeks. Similar effects can be achieved by injecting aqueous microcrystalline suspensions of steroid hormones. More recent attempts have included steroids mixed with cholesterol or lipids and various steroidpermeable membranes.
An early attempt to obtain a longer acting steroid implant comprised mixing of stilbestrol, deoxycorticosterone acetate, testosterone propionate, progesterone, estrone or estradiol benzoate with cholesterol to provide 10, 25, 50, and 100% compositions. Each hormone and each composition was adsorbed differently. The addition of cholesterol, in general retarded adsorption in relation to pellets of pure hormone. However, others have reported an anti-fertility effect in mice with pellets containing 10 or 20% of 19-norprogesterone and 80% cholesterol.
Besides the prolonged action of these steroid preparations, the early studies indicated that except for progesterone these implants were well tolerated by the patients. The most important findings gained from the studies of these steroids was that a pellet of steroid will provide a pharmacological effect at a lower dose than was obtained by injecting an oil solution. The effect of a pellet may last several months.
It appears that two primary delivery systems are preferred by the prior art: steroid-lipid implants and polymer implants. The main difference in these two delivery systems is that permeation of steroids through polymer implants should be predictable. The geometry and total surface area exposed to body fluids remains constant, while with the steroid-lipid implant (other steroid pellets also), during the process of dissolution pattern becomes essentially level.
A number of methods of obtaining prolonged releases are already known. The drug may be enclosed in a capsule which will dissolve in the body after a certain amount of time. In microencapsulation, the drug is enclosed in a large number of very small membrane capsules. Others include tablets coated with lacquers to achieve delayed release; the drug suspended in water, oil, or buffer solution; the drug etherified or esterified to put it in a form in which it is difficult to reabsorb.
Absorption of the drug in carrier materials which can swell, such as gelatin, cellulose, or certain plastics also delays release. Drugs bonded by absorption to large surfaces, release slowly due to the low speed of resorption, such as with adsorbate innoculate or vaccine, a result of a mixture with aluminum hydroxide. If a powdered drug is compressed together with powdered plastics, a porous tablet will form in which the plastic material will partly cover the surface of the powdered drug and will delay its release.